POLYPEPTIDE CONSISTING OF A GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST AND AN AMYLIN RECEPTOR AGONIST, CONNECTED BY A LINKER WITH 4 GLYCINE RESIDUES, AND CONNECTED TO A C18 FATTY ACID SIDE CHAIN

What is on this page?

• What is NNC0487-0111?
• How does NNC0487-0111 work?
• Which conditions is NNC0487-0111 being studied for?
• How is NNC0487-0111 given?
• What do the clinical trials show about conditions studied?
• What phases and status do the trials have?
• What are the trials measuring?
• Who can take part in these trials?

What is NNC0487-0111?

NNC0487-0111 is an investigational medicine being developed by Novo Nordisk A/S. Its full chemical name describes it as a polypeptide consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist and an amylin receptor agonist, connected by a linker with 4 glycine residues, and connected to a C18 fatty acid side chain.^[13] This means the substance is a protein-based molecule designed to activate two different receptors in the body at the same time.

In the EU Clinical Trials Information System (CTIS), the substance appears under the development code NNC0487-0111. It also appears in some trial records under the name zenagamtide. The registry lists the substance as having a marketing authorisation record, but the authorisation holder is listed as Novo Nordisk A/S. In the 12 trials in the CTIS data, NNC0487-0111 is the test substance in 8 trials and serves as a placebo comparator in 12 trial records, meaning the substance is used both as the active treatment and as the basis for placebo arms.^[1]

How does NNC0487-0111 work?

NNC0487-0111 is designed as a single molecule that combines two receptor-activating components: a GLP-1 receptor agonist and an amylin receptor agonist, joined by a linker made of four glycine residues and attached to a C18 fatty acid side chain.^[13] GLP-1 receptor agonists are a class of medicines that help lower blood sugar and reduce body weight by mimicking the action of the natural hormone GLP-1. Amylin receptor agonists mimic the action of amylin, a hormone that also helps regulate blood sugar and appetite. By combining both actions in one molecule, the substance is being investigated for effects on body weight, blood sugar control, and related conditions.

Which conditions is NNC0487-0111 being studied for?

• Obesity — Several Phase 3 trials are testing whether NNC0487-0111 helps people with obesity lose weight and maintain weight loss.
• Type 2 diabetes — A completed Phase 2 trial and several Phase 3 trials are studying the effect on blood sugar control (HbA1c) in people with type 2 diabetes, including those with overweight or obesity.
• Obstructive sleep apnoea — Two Phase 3 trials are investigating whether NNC0487-0111 improves sleep apnoea in people with overweight or obesity, with or without positive airway pressure (PAP) therapy.
• Knee osteoarthritis — Two Phase 3 trials are testing whether NNC0487-0111 reduces knee pain in people with overweight or obesity and knee osteoarthritis.
• Heart failure with obesity — One Phase 3 trial is studying whether NNC0487-0111 reduces the risk of cardiovascular death, heart failure hospitalisation, or urgent heart failure visits in people with heart failure with preserved or mildly reduced ejection fraction and obesity.
• Atherosclerotic cardiovascular disease — One Phase 3 trial is testing whether NNC0487-0111 reduces major cardiovascular events in people with established atherosclerotic cardiovascular disease and overweight or obesity.

How is NNC0487-0111 given?

According to the CTIS product records, NNC0487-0111 is available in two pharmaceutical forms: a tablet for oral use and a solution for injection for subcutaneous use.^[1] The European Medicines Agency (EMA) paediatric investigation plan also lists both tablet and solution for injection forms, with routes of administration being oral use and subcutaneous use.^[13] In the trials, the substance is given subcutaneously in most studies, while the completed Phase 2 trial in type 2 diabetes included both subcutaneous and oral formulations. The registry records do not provide specific dose strengths, as the doses are listed as 0 mg or 0 Other in the trial data.

What do the clinical trials show about conditions studied?

The CTIS data lists 12 clinical trials involving NNC0487-0111. The conditions studied fall into two broad therapeutic areas: nutritional and metabolic diseases, and cardiovascular diseases. The trials cover obesity alone, obesity with type 2 diabetes, obesity with obstructive sleep apnoea, obesity with knee osteoarthritis, heart failure with obesity, and atherosclerotic cardiovascular disease with overweight or obesity.^[1][9] One trial, AMBITION 7, was withdrawn before completion; it was designed to compare zenagamtide with insulin glargine in people with type 2 diabetes and increased cardiovascular risk.^[12]

What phases and status do the trials have?

Of the 12 trials, one is Phase 2 and eleven are Phase 3. The Phase 2 trial in type 2 diabetes is completed; it enrolled 439 participants and measured change in HbA1c from baseline to week 36.^[1] The remaining Phase 3 trials are authorised, meaning they have received regulatory approval to begin but have not yet reported results. One Phase 3 trial, AMBITION 7, was withdrawn.^[12] The largest authorised trial enrolled 8,500 participants with atherosclerotic cardiovascular disease and either overweight or obesity.^[11] The smallest Phase 3 trials enrolled 300 participants each, in obstructive sleep apnoea with or without PAP therapy.^[5][4]

What are the trials measuring?

The primary outcomes vary by condition. In obesity trials, the main measure is the relative change in body weight from baseline.^[10][2] In obstructive sleep apnoea trials, the primary outcomes are relative change in body weight and change in the apnoea-hypopnoea index (AHI), which measures how many times breathing pauses or becomes shallow during sleep.^[5][4] In knee osteoarthritis trials, the primary outcomes are relative change in body weight and change in the WOMAC Osteoarthritis Index pain score, a standard questionnaire that measures knee pain and function.^[6][7] In the heart failure trial, the primary outcome is the time to first occurrence of a composite endpoint consisting of cardiovascular death, heart failure hospitalisation, or urgent heart failure visit.^[9] In the atherosclerotic cardiovascular disease trial, the primary outcome is the time to first occurrence of a 4-point MACE endpoint, which includes cardiovascular death, non-fatal myocardial infarction (heart attack), non-fatal stroke, and heart failure hospitalisation or urgent heart failure visit.^[11] The completed Phase 2 trial in type 2 diabetes measured change in HbA1c, a marker of average blood sugar levels over the previous two to three months.^[1]

Who can take part in these trials?

Each trial has specific eligibility criteria based on the condition being studied. The obesity trials enrol participants with obesity, with some trials also requiring overweight or obesity plus type 2 diabetes.^[10][2] The obstructive sleep apnoea trials enrol participants with overweight or obesity and obstructive sleep apnoea, either treated with positive airway pressure (PAP) therapy or not treated with PAP.^[5][4] The knee osteoarthritis trials enrol participants with overweight or obesity and knee osteoarthritis.^[6][7] The heart failure trial enrols participants with heart failure with preserved or mildly reduced ejection fraction (HFpEF or HFmrEF) and obesity.^[9] The atherosclerotic cardiovascular disease trial enrols participants with established atherosclerotic cardiovascular disease and either overweight or obesity.^[11] The completed Phase 2 trial enrolled participants with type 2 diabetes inadequately controlled with metformin with or without an SGLT2 inhibitor.^[1]